HMGA1a Trapping of U1 snRNP at an Authentic 5′ Splice Site Induces Aberrant Exon Skipping in Sporadic Alzheimer's Disease
- 1 May 2010
- journal article
- Published by Taylor & Francis Ltd in Molecular and Cellular Biology
- Vol. 30 (9), 2220-2228
- https://doi.org/10.1128/mcb.00114-10
Abstract
Overexpression of high-mobility group A protein 1a (HMGA1a) causes aberrant exon 5 skipping of the Presenilin-2 (PS2) pre-mRNA, which is almost exclusively detected in patients with sporadic Alzheimer's disease. An electrophoretic mobility shift assay confirmed aberrant U1 small nuclear ribonucleoprotein particle (snRNP)-HMGA1a complex formation (via the U1-70K component), with RNA containing a specific HMGA1a-binding site and an adjacent 5' splice site. Psoralen cross-linking analysis demonstrated that the binding of HMGA1a adjacent to the 5' splice site induces unusually extended association of U1 snRNP to the 5' splice site. As a result, spliceosome assembly across either the intron or the exon is arrested at an early ATP-independent stage. We conclude that the HMGA1a-induced aberrant exon skipping is caused by impaired dissociation of U1 snRNP from the 5' splice site, leading to a defect in exon definition. The proposed molecular mechanism has profound implications for other known posttranscriptional modulation strategies in various organisms, all of which are triggered by aberrant U1 snRNP binding.Keywords
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